tbuckley/cabot-search huggingface dataset:
Low-temperature photothermal-induced alkyl radical release facilitates dihydroartemisinin-triggered “valve-off” starvation therapy
Authors: Xiaomin Su, Boshu Ouyang, Yao Liu, Yang Wang, Ruizhe Xu, Lili Niu, Nannan Li, Ce Xu, Zanya Sun, Huishu Guo, Zhiqing Pang, Xiangrong Yu
Journal: Asian Journal of Pharmaceutical Sciences (2023)

The high nutrient and energy demand of tumor cells compared to normal cells to sustain rapid proliferation offer a potentially auspicious avenue for implementing starvation therapy. However, conventional starvation therapy, such as glucose exhaustion and vascular thrombosis, can lead to systemic toxicity and exacerbate tumor hypoxia. Herein, we developed a new "valve-off" starvation tactic, which was accomplished by closing the valve of glucose transporter protein 1 (GLUT1). Specifically, dihydroartemisinin (DHA), 2,20-azobis [2-(2-imidazolin-2-yl) propane] dihydrochloride (AI), and Ink were co-encapsulated in a sodium alginate (ALG) hydrogel. Upon irradiation with the 1064 nm laser, AI rapidly disintegrated into alkyl radicals (R•), which exacerbated the DHA-induced mitochondrial damage through the generation of reactive oxygen species and further reduced the synthesis of adenosine triphosphate (ATP). Simultaneously, the production of R• facilitated DHA-induced starvation therapy by suppressing GLUT1, which in turn reduced glucose uptake. Systematic in vivo and in vitro results suggested that this radical-enhanced "valve-off" strategy for inducing tumor cell starvation was effective in reducing glucose uptake and ATP levels. This integrated strategy induces tumor starvation with efficient tumor suppression, creating a new avenue for controlled, precise, and concerted tumor therapy.
Perioperative Treatment Strategies in EGFR-Mutant Early-Stage NSCLC: Current Evidence and Future Challenges
Authors: Jordi Remon, Stephanie P.L. Saw, Francesco Cortiula, Pawan Kumar Singh, Jessica Menis, Giannis Mountzios, Lizza E.L. Hendriks
Journal: Journal of Thoracic Oncology (2023)
Molecular evolution of omicron variant in immunocompromised individuals with chronic SARS-CoV-2 infection
Authors: Camille Vellas, Justine Latour, Pauline Trémeaux, Noémie Ranger, Vénicia Ferrer, Agnès Harter, Romain Carcenac, Pauline Boyer, Sofia Demmou, Pauline Claraz, Nassim Kamar, Jacques Izopet
Journal: Journal of Infection (2023)
Decreasing prevalence of atopic dermatitis in Swedish schoolchildren: three repeated population-based surveys
Authors: Maja af Klinteberg, Anna Winberg, Martin Andersson, Eva Rönmark, Linnea Hedman
Journal: British Journal of Dermatology (2023)

Abstract Background The prevalence of atopic dermatitis (AD) has increased over several decades and now affects about one-fifth of all children in high-income countries (HICs). While the increase continues in lower-income countries, the prevalence of AD might have reached a plateau in HICs. Objectives To investigate trends in the prevalence of AD and atopic comorbidity in schoolchildren in Sweden. Methods The study population consisted of three cohorts of children (median age 8 years) in Norrbotten, Sweden, for 1996 (n = 3430), 2006 (n = 2585) and 2017 (n = 2785). An identical questionnaire that included questions from the International Study of Asthma and Allergies in Childhood (ISAAC) protocol was used in all three cohorts. Trends in AD prevalence were estimated, as well as trends in atopic comorbidity. AD prevalence was estimated both according to the ISAAC definition of AD and by adding the reported diagnosis by a physician (D-AD). Results The prevalence of AD decreased in the last decade, from 22.8% (1996) and 21.3% (2006) to 16.3% (2017; P &amp;lt; 0.001). The prevalence of D-AD was lower, but the same pattern of decrease was seen, from 9.3% (1996) and 9.4% (2006) to 5.7% (2017; P &amp;lt; 0.001). In all three cohorts, AD was more common among girls than boys (18.9% vs. 13.8% in 2017; P &amp;lt; 0.001). Children from the mountain inlands had a higher prevalence of AD than children from coastal cities (22.0% vs. 15.1% in 2017; P &amp;lt; 0.001). In comparing D-AD, there were no significant differences between the sexes or between inland or coastal living. Concomitant asthma increased over the years from 12.2% (1996) to 15.8% (2006) to 23.0% (2017; P &amp;lt; 0.001). Concomitant allergic rhinitis and allergic sensitization increased from 1996 (15.0% and 27.5%) to 2006 (24.7% and 49.5%) but then levelled off until 2017 (21.0% and 46.7%). Conclusions The prevalence of AD among schoolchildren in Sweden decreased over the study period, whereas atopic comorbidity among children with AD increased. Although a decrease was seen, AD is still common and the increase in atopic comorbidity among children with AD, especially the increase in asthma, is concerning.
Fibroblast growth factor receptor 3 mutation attenuates response to immune checkpoint blockade in metastatic urothelial carcinoma by driving immunosuppressive microenvironment
Authors: Yuxuan Song, Yun Peng, Caipeng Qin, Yulong Wang, Wenbo Yang, Yiqing Du, Tao Xu
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Immune checkpoint blockade (ICB) therapy holds promise in metastatic urothelial carcinoma (UC). Fibroblast growth factor receptor 3 (FGFR3) mutation drives T-cell-depleted microenvironment in UC, which led to the hypothesis that FGFR3 mutation might attenuate response to ICB in patients with metastatic UC. The study aims to compare prognosis and response between patients with FGFR3-mutated and FGFR3-wildtype metastatic UC after ICB therapy, and decode the potential molecular mechanisms. Methods Based on the single-arm, multicenter, phase 2 trial, IMvigor210, we conducted a propensity score matched (PSM) analysis. After a 1:1 ratio PSM method, 39 patients with FGFR3-mutated and 39 FGFR3-wildtype metastatic UC treated with atezolizumab were enrolled. A meta-analysis through systematical database retrieval was conducted for validation. In addition, we performed single-cell RNA sequencing on three FGFR3-mutated and three FGFR3-wildtype UC tumors and analyzed 58,069 single cells. Results The PSM analysis indicated FGFR3-mutated patients had worse overall survival (OS) in comparison to FGFR3-wildtype patients (HR=2.11, 95% CI=(1.16 to 3.85), p=0.015) receiving atezolizumab. The median OS was 9.2 months (FGFR3-mutated) versus 21.0 months (FGFR3-wildtype). FGFR3-mutated patients had lower disease control rate than FGFR3-wildtype patients (41.0% vs 66.7%, p=0.023). The meta-analysis involving 938 patients with metastatic UC confirmed FGFR3 mutation was associated with worse OS after ICB (HR=1.28, 95% CI=(1.04 to 1.59), p=0.02). Single-cell RNA transcriptome analysis identified FGFR3-mutated UC carried a stronger immunosuppressive microenvironment compared with FGFR3-wildtype UC. FGFR3-mutated UC exhibited less immune infiltration, and lower T-cell cytotoxicity. Higher TREM2+ macrophage abundance in FGFR3-mutated UC can undermine and suppress the T cells, potentially contributing to the formation of an immunosuppressive microenvironment. Lower inflammatory-cancer-associated fibroblasts in FGFR3-mutated UC recruited less chemokines in antitumor immunity but expressed growth factors to promote FGFR3-mutated malignant cell development. FGFR3-mutated UC carried abundance of malignant cells characterized by high hypoxia/metabolism and low interferon response phenotype. Conclusions FGFR3 mutation can attenuate prognosis and response to ICB in patients with metastatic UC. FGFR3-mutated UC carries a stronger immunosuppressive microenvironment in comparison with FGFR3-wildtype UC. Inhibition of FGFR3 might activate the immune microenvironment, and the combination of FGFR inhibitor targeted therapy and ICB might be a promising therapeutic regimen in metastatic UC, providing important implications for UC clinical management.
Neurovascular dysfunction in glaucoma
Authors: Luis Alarcon-Martinez, Yukihiro Shiga, Deborah Villafranca-Baughman, Jorge L. Cueva Vargas, Isaac A. Vidal Paredes, Heberto Quintero, Brad Fortune, Helen Danesh-Meyer, Adriana Di Polo
Journal: Progress in Retinal and Eye Research (2023)

Retinal ganglion cells, the neurons that die in glaucoma, are endowed with a high metabolism requiring optimal provision of oxygen and nutrients to sustain their activity. The timely regulation of blood flow is, therefore, essential to supply firing neurons in active areas with the oxygen and glucose they need for energy. Many glaucoma patients suffer from vascular deficits including reduced blood flow, impaired autoregulation, neurovascular coupling dysfunction, and blood-retina/brain-barrier breakdown. These processes are tightly regulated by a community of cells known as the neurovascular unit comprising neurons, endothelial cells, pericytes, Müller cells, astrocytes, and microglia. In this review, the neurovascular unit takes center stage as we examine the ability of its members to regulate neurovascular interactions and how their function might be altered during glaucomatous stress. Pericytes receive special attention based on recent data demonstrating their key role in the regulation of neurovascular coupling in physiological and pathological conditions. Of particular interest is the discovery and characterization of tunneling nanotubes, thin actin-based conduits that connect distal pericytes, which play essential roles in the complex spatial and temporal distribution of blood within the retinal capillary network. We discuss cellular and molecular mechanisms of neurovascular interactions and their pathophysiological implications, while highlighting opportunities to develop strategies for vascular protection and regeneration to improve functional outcomes in glaucoma.
Increased risk of recurrence and disease-specific death following delayed postoperative radiation for Merkel cell carcinoma
Authors: Nora A. Alexander, Stephanie K. Schaub, Peter H. Goff, Daniel S. Hippe, Song Y. Park, Kristina Lachance, Marika Bierma, Jay J. Liao, Smith Apisarnthanarax, Shailender Bhatia, Yolanda D. Tseng, Paul T. Nghiem, Upendra Parvathaneni
Journal: Journal of the American Academy of Dermatology (2023)
Hepatocyte nuclear factor 4α mediated quinolinate phosphoribosylltransferase (QPRT) expression in the kidney facilitates resilience against acute kidney injury
Authors: Amanda J. Clark, Marie Christelle Saade, Vamsidhara Vemireddy, Kyle Q. Vu, Brenda Mendoza Flores, Valerie Etzrodt, Erin J. Ciampa, Huihui Huang, Ayumi Takakura, Kambiz Zandi-Nejad, Zsuzsanna K. Zsengellér, Samir M. Parikh
Journal: Kidney International (2023)
EYA4 promotes breast cancer progression and metastasis through its role in replication stress avoidance
Authors: Bárbara de la Peña Avalos, Romain Tropée, Pascal H. G. Duijf, Eloïse Dray
Journal: Molecular Cancer (2023)

The Eyes Absent (EYA) family of proteins is an atypical group of four dual-functioning protein phosphatases (PP), which have been linked to many vital cellular processes and organogenesis pathways. The four family members of this PP family possess transcriptional activation and phosphatase functions, with serine/threonine and tyrosine phosphatase domains. EYA4 has been associated with several human cancers, with tumor-suppressing and tumor-promoting roles. However, EYA4 is the least well-characterized member of this unique family of PP, with its biological functions and molecular mechanisms in cancer progression, particularly in breast cancer, still largely unknown. In the present study, we found that the over-expression of EYA4 in breast tissue leads to an aggressive and invasive breast cancer phenotype, while the inhibition of EYA4 reduced tumorigenic properties of breast cancer cells in vitro and in vivo. Cellular changes downstream of EYA4, including cell proliferation and migration, may explain the increased metastatic power of breast cancer cells over-expressing EYA4. Mechanistically, EYA4 prevents genome instability by inhibiting the accumulation of replication-associated DNA damage. Its depletion results in polyploidy as a consequence of endoreplication, a phenomenon that can occur in response to stress. The absence of EYA4 leads to spontaneous replication stress characterized by the activation of the ATR pathway, sensitivity to hydroxyurea, and accumulation of endogenous DNA damage as indicated by increased γH2AX levels. In addition, we show that EYA4, specifically its serine/threonine phosphatase domain, plays an important and so far, unexpected role in replication fork progression. This phosphatase activity is essential for breast cancer progression and metastasis. Taken together, our data indicate that EYA4 is a novel potential breast cancer oncogene that supports primary tumor growth and metastasis. Developing therapeutics aimed at the serine/threonine phosphatase activity of EYA4 represents a robust strategy for killing breast cancer cells, to limit metastasis and overcome chemotherapy resistance caused by endoreplication and genomic rearrangements.
Five-year Outcomes of Transcatheter Edge-to-Edge Repair in Patients with Mitral Regurgitation and Cardiogenic Shock
Authors: Aleksander Dokollari, Aleksander Dokollari, Basel Ramlawi, Eric Gnall, Harish Jarrett, Katherine Hawthorne, Nitin Ghorparde, Ozgun Erten, Roberto Rodriguez, Sandra Abramson, Scott Goldman, Serge Sicouri, William Gray
Journal: International Journal of Surgery (2023)

Objective: To analyze five-year clinical and echocardiographic outcomes in patients presenting with acute cardiogenic shock (CS) who underwent transcatheter edge-to-edge repair (TEER) for moderate or severe mitral valve regurgitation (MR). Methods: All consecutive patients who underwent TEER for MR were identified from our institutional medical records between 2015 and 2022. Patients presenting with CS undergoing TEER were included in the primary analysis. MR was diagnosed based on patient's echocardiographic findings and CS was diagnosed according to the definition in the TVT registry and/or presence of inotrope use prior to procedure and/or mechanical circulatory support prior to procedure. Kaplan-Meier survival curves were constructed to analyze outcomes. Primary outcome was five-year incidence of all-cause death. Secondary outcomes were major adverse cardiovascular and cerebrovascular events (MACCE) and readmission for heart failure (HF). Results: A total of 35 patients were included in the study. Mean age was 81±10.4 years and 16 patients (45.7%) were male. Mean STS-score was 10.2±7.1. Nine (25.7%) patients had prior myocardial infarction (MI), 22 (62.8%) had previous atrial fibrillation, while 9 (25.7%) patients were hospitalized for HF within the past year. MR etiology was degenerative (71.4%), functional (22.9%), and mixed (5.7%). Prior to presentation with CS, NYHA classification included 2 (5,7%) patients in class I, 6 (17.1%) in class II, 13 (37.1%) in class III, and 14 (40%) in class IV. Pre-procedural mean LVEF was 56.4 ± 13%. Procedural characteristics included mean procedural time (from access to guide removal) of 2.0 ± 0.6 hours, &gt; 1 implanted device in 14 (40.0%) patients, 1 patient had a single leaflet attachment. There was no procedural device embolism, device thrombosis, conversion to sternotomy, life threatening bleeding, stroke, MI, or death. Mean postoperative length of stay was 5.1 ± 4.4 days. During their hospital stay, a transient ischemic attack event occurred in 1 patient; however, no MI, stroke, or death were observed in any patient. During the follow-up, 13 (37.1%) patients were readmitted for HF, 1 patient needed mitral valve replacement and 1 patient needed new TEER. At 5 years, only 4 (11.4%) patients were alive. Conclusion: Despite excellent procedural and early outcomes for patients with significant MR and CS undergoing TEER, poor survival was observed after 5 years, which may be related to advanced age of this cohort.
Injectable polyisocyanide hydrogel as healing supplement for connective tissue regeneration in an abdominal wound model
Authors: Aksel N. Gudde, Melissa J.J. van Velthoven, Paul H.J. Kouwer, Jan-Paul W.R. Roovers, Zeliha Guler
Journal: Biomaterials (2023)

In pelvic organ prolapse (POP) patients, the uterus, bladder and/or rectum descends into vagina due to weakened support tissues. High recurrence rates after POP surgery suggest an urgent need for improved surgical outcomes. Our aim is to promote connective tissue healing that results in stimulated tissue support functions by surgically applying a hydrogel functionalized with biological cues. We used known vaginal wound healing promoting factors (basic fibroblast growth factor, β-estradiol, adipose-derived stem cells) in the biomimetic and injectable polyisocyanide (PIC) hydrogel, which in itself induces regenerative vaginal fibroblast behavior. The regenerative capacity of injected PIC hydrogel, and the additional pro-regenerative effects of these bioactive factors was evaluated in abdominal wounds in rabbits. Assessment of connective tissue healing (tensile testing, histology, immunohistochemistry) revealed that injection with all PIC formulations resulted in a statistically significant stiffness and collagen increase over time, in contrast to sham. Histological evaluation indicated new tissue growth with moderate to mild immune activity at the hydrogel - tissue interface. The results suggest that PIC injection in an abdominal wound improves healing towards regaining load-bearing capacity, which encourages us to investigate application of the hydrogel in a more translational vaginal model for POP surgery in sheep.
Efficient drug supply in stem cell cytosol via pore-forming saponin nanoparticles promotes in vivo osteogenesis and bone regeneration
Authors: Ji Sun Park, Chaehyun Lee, Seo Young Cheon, Yeeun Lee, Hayoung Jeon, Donghyun Lee, Se Hee Kim, Seong Gi Lim, Heebeom Koo
Journal: Biomaterials (2023)
The effect of lengths of branched-chain fatty alcohols on the efficacy and safety of docetaxel-prodrug nanoassemblies
Authors: Shuo Wang, Tian Liu, Yuetong Huang, Chaoying Du, Danping Wang, Xiyan Wang, Qingzhi Lv, Zhonggui He, Yinglei Zhai, Bingjun Sun, Jin Sun
Journal: Acta Pharmaceutica Sinica B (2023)

The self-assembly prodrugs are usually consisted of drug modules, activation modules, and assembly modules. Keeping the balance between efficacy and safety by selecting suitable modules remains a challenge for developing prodrug nanoassemblies. This study designed four docetaxel (DTX) prodrugs using disulfide bonds as activation modules and different lengths of branched-chain fatty alcohols as assembly modules (C16, C18, C20, and C24). The lengths of the assembly modules determined the self-assembly ability of prodrugs and affected the activation modules' sensitivity. The extension of the carbon chains improved the prodrugs' self-assembly ability and pharmacokinetic behavior while reducing the cytotoxicity and increased cumulative toxicity. The use of C20 can balance efficacy and safety. These results provide a great reference for the rational design of prodrug nanoassemblies.
High dose, dual-release polymeric films for extended surgical bed paclitaxel delivery
Authors: David A. Mahvi, Jenny Korunes-Miller, Catalina Bordeianu, Ngoc-Quynh Chu, Abraham D. Geller, Robbie Sabatelle, Samantha Berry, Yin P. Hung, Yolonda L. Colson, Mark W. Grinstaff, Chandrajit P. Raut
Journal: Journal of Controlled Release (2023)
The biomolecular gastrointestinal corona in oral drug delivery
Authors: Anas Aljabbari, Shinji Kihara, Thomas Rades, Ben J. Boyd
Journal: Journal of Controlled Release (2023)

The formation of a biomolecular corona on exogenous particles in plasma is well studied and is known to dictate the biodistribution and cellular interactions of nanomedicine formulations. In contrast, while the oral route is the most favorable administration method for pharmaceuticals, little is known about the formation and composition of the corona formed by biomolecules on particles within the gastrointestinal tract. This work reviews the current literature understanding of (1) the formation of drug particles after oral administration, (2) the formation of a biomolecular corona within the gastrointestinal tract ("the gastrointestinal corona"), and (3) the possible implications of the formation of a gastrointestinal corona on the interactions of drug particles with their biological environment. In doing so, this work aims to establish the significance of the formation of a gastrointestinal corona in oral drug delivery to ultimately arrive at new avenues to control the behavior of orally administered pharmaceuticals.
Reducing the Risks of Nuclear War: The Role of Health Professionals
Authors: Kamran Abbasi, Parveen Ali, Virginia Barbour, Kirsten Bibbins-Domingo, Peng Gong, Andy Haines, Ira Helfand, Richard Horton, Bob Mash, Arun Mitra, Carlos Monteiro, Elena N. Naumova, Marcel G.M. Olde Rikkert, Eric J. Rubin, Tilman Ruff, Peush Sahni, James Tumwine, Paul Yonga, Chris Zielinski
Journal: American Journal of Psychiatry (2023)
STING activation promotes autologous type I interferon–dependent development of type 1 regulatory T cells during malaria
Authors: Yulin Wang, Fabian De Labastida Rivera, Chelsea L. Edwards, Teija C.M. Frame, Jessica A. Engel, Luzia Bukali, Jinrui Na, Susanna S. Ng, Dillon Corvino, Marcela Montes de Oca, Patrick T. Bunn, Megan S.F. Soon, Dean Andrew, Jessica R. Loughland, Jia Zhang, Fiona H. Amante, Bridget E. Barber, James S. McCarthy, J. Alejandro Lopez, Michelle J. Boyle, Christian R. Engwerda
Journal: Journal of Clinical Investigation (2023)

The development of highly effective malaria vaccines and improvement of drug-treatment protocols to boost antiparasitic immunity are critical for malaria elimination. However, the rapid establishment of parasite-specific immune regulatory networks following exposure to malaria parasites hampers these efforts. Here, we identified stimulator of interferon genes (STING) as a critical mediator of type I interferon production by CD4+ T cells during blood-stage Plasmodium falciparum infection. The activation of STING in CD4+ T cells by cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) stimulated IFNB gene transcription, which promoted development of IL-10- and IFN-γ-coproducing CD4+ T (type I regulatory [Tr1]) cells. The critical role for type I IFN signaling for Tr1 cell development was confirmed in vivo using a preclinical malaria model. CD4+ T cell sensitivity to STING phosphorylation was increased in healthy volunteers following P. falciparum infection, particularly in Tr1 cells. These findings identified STING expressed by CD4+ T cells as an important mediator of type I IFN production and Tr1 cell development and activation during malaria.